Jan Van Keer

Proteasome inhibitor associated thrombotic microangiopathy

A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug‐induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin—7.5 g dL−1, platelet count—20 × 109/L, LDH—698 U L−1, creatinine—3.12 mg dL−1. No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348–E352, 2016.

Pulmonary outflow obstruction protects against heart failure in adults with congenitally corrected transposition of the great arteries

BACKGROUND Pulmonary outflow tract obstruction (POTO) reduces systemic atrioventricular valve (SAVV) regurgitation severity in congenitally corrected transposition of the great arteries (ccTGA). Therefore, pulmonary artery banding is proposed as a palliative intervention. We aimed to investigate the effect of native or surgically induced POTO on event-free survival, defined as the composite of all-cause mortality, heart transplantation, or congestive heart failure (CHF). METHODS AND RESULTS Patients with ccTGA (n=62; median age 27.5 (IQR 18.4-39.4) years; 39% with POTO) were selected from the Adult Congenital Heart Disease database of a tertiary hospital. At first visit, SAVV regurgitation ≥ 3/4, systemic RV dysfunction ≥ moderate, and CHF were present in 26%, 26%, and 15% of patients, respectively. Over a mean follow-up time of 10.1 ± 6.1 years, all-cause mortality, rate of heart transplantation, and CHF were 18%, 8% and 40%, respectively. SAVV regurgitation (HR: 1.99; 95% CI: 1.01-3.92; P=0.048) and systemic RV dysfunction severity (HR: 1.89; 95% CI: 1.05-3.37; P=0.033) were associated with the composite endpoint, independently of age at baseline, POTO, Ebstein-like malformation, and systemic RV dilatation. Patients with POTO had lower risk for developing SAVV regurgitation ≥ 3/4 (HR: 0.18; 95% CI: 0.05-0.58; P=0.004) and moderate systemic RV dysfunction (HR: 0.34; 95% CI: 0.15-0.78; P=0.011). When POTO was present, the mean progression-free interval for the composite endpoint increased from 11.2 to 18.1 years (P=0.035). CONCLUSIONS POTO is associated with an improved event-free survival in adults with ccTGA.

More Than Meets the Eye: Klebsiella pneumoniae Invasive Liver Abscess Syndrome Presenting with Endophthalmitis

BACKGROUND Endophthalmitis is a feared complication of pyogenic liver abscesses caused by hypervirulent Klebsiella pneumoniae strains. First described in East Asia in the 1980s, this invasive syndrome is only recently emerging in Europe and America. CASE REPORT We describe an 84-year-old man who presented to the emergency department with fever, orbital cellulitis, and bilateral visual loss. Although the patient had no overt abdominal symptoms, computed tomography scan revealed a pyogenic liver abscess. Blood cultures were positive for K. pneumoniae. Initial treatment consisted of intravenous ceftriaxone and intravitreal ceftazidime. A unilateral vitrectomy was performed. The patient survived with severe visual sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: K. pneumoniae pyogenic liver abscess with metastatic endophthalmitis is a relatively new syndrome that should be considered in patients presenting with acute vision loss who appear septic, with or without abdominal complaints. Early recognition prohibits delays in lifesaving treatment.

Non-invasive assessment of cerebral oxygenation: A comparison of retinal and transcranial oximetry

Background To investigate the correlation between cerebral (SO2-transcranial), retinal arterial (SaO2-retinal) and venous (SvO2-retinal) oxygen saturation as measured by near-infrared spectroscopy (NIRS) and retinal oximetry respectively. Methods Paired retinal and cerebral oxygen saturation measurements were performed in healthy volunteers. Arterial and venous retinal oxygen saturation and diameter were measured using a non-invasive spectrophotometric retinal oximeter. Cerebral oxygen saturation was measured using near-infrared spectroscopy. Correlations between SO2-transcranial and retinal oxygen saturation and diameter measurements were assessed using Pearson correlation coefficients. Lin’s concordance correlation coefficient (CCC) and Bland-Altman analysis were performed to evaluate the agreement between SO2-transcranial as measured by NIRS and as estimated using a fixed arterial:venous ratio as 0.3 x SaO2-retinal + 0.7 x SvO2-retinal. The individual relative weight of SaO2-retinal and SvO2-retinal to obtain the measured SO2-transcranial was calculated for all subjects. Results Twenty-one healthy individuals aged 26.4 ± 2.2 years were analyzed. SO2-transcranial was positively correlated with both SaO2-retinal and SvO2-retinal (r = 0.44, p = 0.045 and r = 0.43, p = 0.049 respectively) and negatively correlated with retinal venous diameter (r = -0.51, p = 0.017). Estimated SO2-transcranial based on retinal oximetry showed a tolerance interval of (-13.70 to 14.72) and CCC of 0.46 (95% confidence interval: 0.05 to 0.73) with measured SO2-transcranial. The average relative weights of SaO2-retinal and SvO2-retinal to obtain SO2-transcranial were 0.31 ± 0.11 and 0.69 ± 0.11, respectively. Conclusion This is the first study to show the correlation between retinal and cerebral oxygen saturation, measured by NIRS and retinal oximetry. The average relative weight of arterial and venous retinal oxygen saturation to obtain the measured transcranial oxygen saturation as measured by NIRS, approximates the established arterial:venous ratio of 30:70 closely, but shows substantial inter-individual variation. These findings provide a proof of concept for the role of retinal oximetry in evaluating cerebral oxygenation.

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

Two Cases of Heavy Chain MGUS

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

Urinary proteomic signatures associated with β-blockade and heart rate in heart transplant recipients

Objectives Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on β-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature. Methods In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins. Results In adjusted analyses, HF1, HF2 and CKD273 (p ≤ 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p ≥ 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p ≤ 0.014). There were no differences in the urinary biomarkers (p ≥ 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments. Conclusions BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial.

Urinary peptidomic biomarkers of renal function in heart transplant recipients

Abstract Background Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). Methods In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. Results In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25–15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56–4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70–0.80) than 24-h proteinuria (0.64; 95% CI 0.58–0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. Conclusions With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1—respectively, positively and inversely associated with eGFR and change in eGFR—are single-peptide markers associated with renal dysfunction.

Diastolic left ventricular function in relation to circulating metabolic biomarkers in a population study

Aims We studied the association of circulating metabolic biomarkers with asymptomatic left ventricular diastolic dysfunction, a risk-carrying condition that affects 25% of the population. Methods and results In 570 randomly recruited people, we assessed in 2005–2010 and in 2009–2013 the multivariable-adjusted correlations of e’ (early left ventricular relaxation) and E/e’ (left ventricular filling pressure) measured by Doppler echocardiography with 43 serum metabolites, quantified by magnetic resonance spectroscopy. In 2009–2013, e’ cross-sectionally increased (Bonferroni corrected p ≤ 0.016) with the branched-chain amino acid valine (per one standard deviation increment, +0.274 cm/s (95% confidence interval, 0.057–0.491)) and glucose+the amino acid (AA) taurine (+0.258 cm/s (0.067–0.481)), while E/e’ decreased (p ≤ 0.017) with valine (–0.264 (–0.496– –0.031)). The risk of developing left ventricular diastolic dysfunction over follow-up (9.4%) was inversely associated (p ≤ 0.0059) with baseline glucose+amino acid taurine (odds ratio, 0.64 (0.44–0.94). In partial least squares analyses of all the baseline and follow-up data, markers consistently associated with better diastolic left ventricular function included the amino acids 2-aminobutyrate and 4-hydroxybutyrate and the branched-chain amino acids leucine and valine, and those consistently associated with worse diastolic left ventricular function glucose+amino acid glutamine and fatty acid pentanoate. Branched-chain amino acid metabolism (–log10 p  = 12.6) and aminoacyl-tRNA biosynthesis (9.9) were among the top metabolic pathways associated with left ventricular diastolic dysfunction. Conclusion The associations of left ventricular diastolic dysfunction with circulating amino acids and branched-chain amino acids were consistent over a five-year interval and suggested a key role of branched-chain amino acid metabolism and aminoacyl-tRNA biosynthesis in maintaining diastolic left ventricular function.

Retinal oxygen saturation as a non-invasive estimate for mixed venous oxygen saturation and cardiac output

To investigate the correlation between retinal vessel oxygen saturation and mixed venous oxygen saturation (SvO2‐mixed) and cardiac output (CO).